ABSTRACT Delirium is a common, costly, life-threatening, and potentially preventable problem for older persons, yet its pathophysiology remains poorly understood. The development of delirium is considered to be a marker of brain vulnerability; however, its relationship to dementia remains unclear. During the first cycle, we successfully completed 4 projects centered around a cohort of >560 older surgical patients (SAGES I), which documented: an accelerated trajectory of long-term cognitive decline following delirium (Project 1); and important risk markers for delirium, related to inflammation (Project 2), structural dysconnectivity (Project 3), and impairment in global cognitive performance (Project 4). These important findings have paved the way for us to move forward to extend our pathophysiologic understanding through innovative probes of brain vulnerability. We now propose a series of 5 interlinked projects applying innovative approaches to deepen our exploration of pathophysiologic pathways potentially contributing to delirium and its associated cognitive decline. We will examine the role of inflammation with state-of-the-art approaches in Project 2; Alzheimer's disease (AD) biomarkers (cerebrospinal fluid, CSF) in Project 1,and neuroimaging markers in Project 3); and measures of brain plasticity/connectivity (transcranial magnetic stimulation and evoked potentials) in Project 5. These approaches were chosen based on their innovation, potential to probe vulnerability, and ability to advance our mechanistic understanding. Project 4 will identify and validate predictors of complicated delirium, i.e., delirium associated with long-term cognitive decline. All of these studies will utilize both the original SAGES I cohort, and a new prospectively enrolled cohort, SAGES II (N=400), which will include CSF sampling obtained prior to spinal anesthesia. All projects will be supported by our effective infrastructure of 3 cores: Administrative (Core A), Field (Core B), and Data Management and Statistical Analysis (Core C). This Program Project renewal proposal brings together an expert, interdisciplinary group in a supportive environment to address a highly clinically relevant area in an integrated and coordinated fashion. The proposal is truly innovative with novel pathophysiologic approaches, extensive cross-linking aims, and multiple methodologic innovations. Furthermore, the large, well-defined cohort created in the first cycle (SAGES I) presents an unprecedented opportunity to explore long-term the relationship of delirium, cognitive decline, and Alzheimer's disease, lending some urgency to this renewal. The highly integrated nature of all the projects could not be achieved without this program project infrastructure, representing a major strength and source of efficiency. This infrastructure provides the capacity to execute five projects and cross-linking aims, expanding the breadth of our pathophysiologic investigation in far-reaching directions. Ultimately, this project holds tremendous potential to advance our understanding of delirium, its attendant complications, and to develop more effective strategies for prevention and treatment.